One of the major challenges for the pharmaceutical industry is drug delivery into the central nervous system (CNS). More than 95% of potentially useful drugs are prevented from entering the CNS due to the protective function of the blood-brain barrier, formed by microvascular endothelium and astrocytes. The key elements of the barrier are continuous tight-junctions between endothelial cells, which prevent molecules from diffusing into the brain, and ABC-transporters that actively pump xenobiotics out of the brain (1, 2). As a result, many drugs and larger biomolecules, including cytokines and genes which have considerable potential for the treatment of CNS disease, are excluded by the endothelial barrier (3-6).
Considerable efforts have been made to find a way of overcoming the blood-brain barrier, including the use of nanoparticles as a carrier (7). Biologically interesting nano- and micro-particles ranging from 1 nm to 500 nm have been made from materials such as polymers, lipids and metals, including gold. Gold nanoparticles have the advantage of easy production and chemical stability, and they have been recently used in nanomedicine for both diagnosis and therapy (8). The gold core is inert but it does interact with biological material and can have biological effects. To address this, a variety of sizes and surface modifications have been investigated which affect the specific behaviour of the nanoparticles (9-11). The transport into a cell is a property which can vary significantly depending on size and surface coating (12). Small-sized gold nanoparticles (>30 nm) are able to enter cells via an endocytic pathway (13, 14) although the mechanism of the transport is not exactly known. It is thought that gold nanoparticles do not enter the nucleus (15) unless the cell is apoptotic. In contrast, they are often trapped in vesicles (16-19) which can cause a problem for targeted drug/gene delivery into the cell and tissues in general.
Hence, focusing on the CNS and the blood-brain barrier, there remains an unmet need for a CNS nanoparticle-based molecular delivery, in particular exhibiting one or more of the following features:
1. Selectivity for the brain endothelium
2. Ability to cross the brain endothelium intact
3. Uptake by the target cell within the CNS.
The present invention addresses these and other needs.